Study uncovers roles of certain brain cells in Alzheimer’s plaque formation

This is evident from a recent study published in the journal Nature Neuroscience, researchers examined the contributions of oligodendrocytes (OLs) and neurons to the burden of amyloid-β (Aβ) plaques in model mice with Alzheimer’s disease (AD). They found that OLs and neurons contribute to the Aβ plaque burden, requiring excitatory projection neurons to provide a threshold level of Aβ for rapid plaque seeding. The findings are valuable for understanding AD prevention and could potentially inform therapeutic strategies.

Study: Oligodendrocytes produce amyloid-β and contribute to plaque formation next to neurons in Alzheimer’s disease model mice. Image credits: Jose Luis Calvo / Shutterstock

Background

AD is a progressive neurodegenerative disorder characterized by memory loss, cognitive decline, and behavioral changes. It often leads to dementia in older adults. It involves the accumulation of Aβ plaques and neurofibrillary tangles in the brain, leading to the death of brain cells and the deterioration of brain function. Evidence suggests that Aβ production is mainly associated with excitatory neurons (ExNs). However, recent studies suggest that other cell types can also produce Aβ. Studies have shown that cultured OLs can generate detectable levels of Aβ in vitro. Given that OL lineage cells are abundant in both gray and white matter, and myelin changes are known to be associated with AD, researchers in the current study examined whether OLs contribute to Aβ plaque burden. in vivo. They aimed to understand the role of OLs in AD, potentially revealing new insights into how different cell types contribute to disease progression, potentially opening new avenues for treatment strategies.

About the study

The researchers analyzed single-nucleus ribonucleic acid sequencing (snRNA-seq) and single-cell RNA sequencing (scRNA-seq) datasets from wild-type mouse and human nervous systems, to analyze the expression of amyloidogenic pathway genes, including APP (amyloid precursor protein). ), BACE1 (beta-site APP-cleaving enzyme 1), PSEN1 (presenilin 1), and PSEN2 (presenilin 2) in major cell populations of the central nervous system (CNS). CNS cell populations, including excitatory neurons, inhibitory neurons, oligodendrocyte precursor cells, mature oligodendrocytes, astrocytes, microglia, endothelial cells, and pericytes, were used for analysis. Furthermore, the researchers validated the expression of APP in mouse and human OLs using several techniques, including immunolabeling and in situ hybridization (ISH). New AD mouse lines were established to assess the contribution of OLs and ExNs to Aβ production. The APP^NLGF knock-in mice were crossed with Bace1fl/fl mice to conditionally knock out (cKO) Bace1 in specific cell types using Cnp-Cre for OLs and Nex-Cre for ExNs. Changes in APP processing were analyzed by Western blotting. Light sheet microscopy (LSM) was used to image amyloid plaques in mouse brains, and an electrochemiluminescence assay was used to measure Aβ levels.

Results and discussion

According to the study, both neurons and OLs were found to express genes for the amyloidogenic pathway. APP expression in OLs was confirmed in both mouse and human tissues. New AD mouse lines revealed a 30% reduction in plaque burden in OL-Bace1^cKO;AD mice compared to controls, while ExN-Bace1^cKO;AD mice showed a 95-98% reduction. This indicated that ExN-derived Aβ is crucial for plaque formation. Despite the high expression of amyloidogenic genes in OLs, their contribution to overall Aβ deposition was smaller compared to neurons.

Plaque burden was found to be nonlinearly related to Aβ production, with neuronal Aβ being essential for reaching the threshold level for plaque seeding. Residual Aβ production in ExN-Bace1^cKO;AD brains were mainly derived from OLs. Functional analysis showed no changes in neuronal or axonal abundance due to Bace1 cKO, and myelin profiles remained unchanged. The findings suggest that although OLs contribute to Aβ production, their efficiency in generating Aβ is lower than that of neurons.

Working model for modulating cell type-specific Aβ contributions. Selectively removing Aβ from specific cell types results in a stable rate change of Aβ production, causing exponentially slower plaque growth that follows a sigmoidal growth curve. ctrl, control; rel., relative.

Conclusion

In conclusion, the study provides the former in vivo evidence that OLs contribute significantly to AD by establishing primary Aβ pathology. The reduction in plaques in mice was comparable to the effects of antibody therapies with aducanumab and lecanemab. Although ExN-derived Aβ remains necessary for rapid plaque formation, the current discovery shifts some focus from exclusively ExNs to OLs in AD pathology. The findings also suggest that specifically targeting BACE1 in OLs could provide a therapeutic strategy with fewer side effects compared to widespread BACE1 inhibition. Furthermore, it supports the potential of BACE1 inhibitors in preventing amyloidosis if administered before Aβ reaches harmful levels, providing new insights for the development of more effective AD treatments.

I am happy to have completed part of my PhD @NatuurNeuro ✨ Oligodendrocytes (OL) contribute to the Aβ plaque load in addition to excitatory neurons, the latter being crucial for local and distal seeding of plaques. Also shown is the nonlinearity between Aβ levels and plaque burden.https://t.co/hsWysuXPzu

— Andrew Octavian Sasmita (@AOSasmita) August 5, 2024